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Efficacy and safety of anti-CD45–saporin as conditioning agent for RAG deficiency
BACKGROUND: Mutations in the recombinase-activating genes cause severe immunodeficiency, with a spectrum of phenotypes ranging from severe combined immunodeficiency to immune dysregulation. Hematopoietic stem cell transplantation is the only curative option, but a high risk of graft failure and poor...
Autores principales: | , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8322962/ https://www.ncbi.nlm.nih.gov/pubmed/32387109 http://dx.doi.org/10.1016/j.jaci.2020.04.033 |
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author | Castiello, Maria Carmina Bosticardo, Marita Sacchetti, Nicolò Calzoni, Enrica Fontana, Elena Yamazaki, Yasuhiro Draghici, Elena Corsino, Cristina Bortolomai, Ileana Sereni, Lucia Yu, Hsin-Hui Uva, Paolo Palchaudhuri, Rahul Scadden, David T. Villa, Anna Notarangelo, Luigi D. |
author_facet | Castiello, Maria Carmina Bosticardo, Marita Sacchetti, Nicolò Calzoni, Enrica Fontana, Elena Yamazaki, Yasuhiro Draghici, Elena Corsino, Cristina Bortolomai, Ileana Sereni, Lucia Yu, Hsin-Hui Uva, Paolo Palchaudhuri, Rahul Scadden, David T. Villa, Anna Notarangelo, Luigi D. |
author_sort | Castiello, Maria Carmina |
collection | PubMed |
description | BACKGROUND: Mutations in the recombinase-activating genes cause severe immunodeficiency, with a spectrum of phenotypes ranging from severe combined immunodeficiency to immune dysregulation. Hematopoietic stem cell transplantation is the only curative option, but a high risk of graft failure and poor immune reconstitution have been observed in the absence of myeloablation. OBJECTIVES: Our aim was to improve multilineage engraftment; we tested nongenotoxic conditioning with anti-CD45 mAbs conjugated with saporin CD45 (CD45-SAP). METHODS: Rag1-KO and Rag1-F971L mice, which represent models of severe combined immune deficiency and combined immune deficiency with immune dysregulation, respectively, were conditioned with CD45-SAP, CD45-SAP plus 2 Gy of total body irradiation (TBI), 2 Gy of TBI, 8 Gy of TBI, or no conditioning and treated by using transplantation with lineage-negative bone marrow cells from wild-type mice. Flow cytometry and immunohistochemistry were used to assess engraftment and immune reconstitution. Antibody responses to 2,4,6-trinitrophenyl–conjugated keyhole limpet hemocyanin were measured by ELISA, and presence of autoantibody was detected by microarray. RESULTS: Conditioning with CD45-SAP enabled high levels of multilineage engraftment in both Rag1 mutant models, allowed overcoming of B- and T-cell differentiation blocks and thymic epithelial cell defects, and induced robust cellular and humoral immunity in the periphery. CONCLUSIONS: Conditioning with CD45-SAP allows multilineage engraftment and robust immune reconstitution in mice with either null or hypomorphic Rag mutations while preserving thymic epithelial cell homeostasis. |
format | Online Article Text |
id | pubmed-8322962 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
record_format | MEDLINE/PubMed |
spelling | pubmed-83229622021-07-30 Efficacy and safety of anti-CD45–saporin as conditioning agent for RAG deficiency Castiello, Maria Carmina Bosticardo, Marita Sacchetti, Nicolò Calzoni, Enrica Fontana, Elena Yamazaki, Yasuhiro Draghici, Elena Corsino, Cristina Bortolomai, Ileana Sereni, Lucia Yu, Hsin-Hui Uva, Paolo Palchaudhuri, Rahul Scadden, David T. Villa, Anna Notarangelo, Luigi D. J Allergy Clin Immunol Article BACKGROUND: Mutations in the recombinase-activating genes cause severe immunodeficiency, with a spectrum of phenotypes ranging from severe combined immunodeficiency to immune dysregulation. Hematopoietic stem cell transplantation is the only curative option, but a high risk of graft failure and poor immune reconstitution have been observed in the absence of myeloablation. OBJECTIVES: Our aim was to improve multilineage engraftment; we tested nongenotoxic conditioning with anti-CD45 mAbs conjugated with saporin CD45 (CD45-SAP). METHODS: Rag1-KO and Rag1-F971L mice, which represent models of severe combined immune deficiency and combined immune deficiency with immune dysregulation, respectively, were conditioned with CD45-SAP, CD45-SAP plus 2 Gy of total body irradiation (TBI), 2 Gy of TBI, 8 Gy of TBI, or no conditioning and treated by using transplantation with lineage-negative bone marrow cells from wild-type mice. Flow cytometry and immunohistochemistry were used to assess engraftment and immune reconstitution. Antibody responses to 2,4,6-trinitrophenyl–conjugated keyhole limpet hemocyanin were measured by ELISA, and presence of autoantibody was detected by microarray. RESULTS: Conditioning with CD45-SAP enabled high levels of multilineage engraftment in both Rag1 mutant models, allowed overcoming of B- and T-cell differentiation blocks and thymic epithelial cell defects, and induced robust cellular and humoral immunity in the periphery. CONCLUSIONS: Conditioning with CD45-SAP allows multilineage engraftment and robust immune reconstitution in mice with either null or hypomorphic Rag mutations while preserving thymic epithelial cell homeostasis. 2020-05-06 2021-01 /pmc/articles/PMC8322962/ /pubmed/32387109 http://dx.doi.org/10.1016/j.jaci.2020.04.033 Text en https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/ (https://creativecommons.org/licenses/by-nc-nd/4.0/) ). |
spellingShingle | Article Castiello, Maria Carmina Bosticardo, Marita Sacchetti, Nicolò Calzoni, Enrica Fontana, Elena Yamazaki, Yasuhiro Draghici, Elena Corsino, Cristina Bortolomai, Ileana Sereni, Lucia Yu, Hsin-Hui Uva, Paolo Palchaudhuri, Rahul Scadden, David T. Villa, Anna Notarangelo, Luigi D. Efficacy and safety of anti-CD45–saporin as conditioning agent for RAG deficiency |
title | Efficacy and safety of anti-CD45–saporin as conditioning agent for RAG deficiency |
title_full | Efficacy and safety of anti-CD45–saporin as conditioning agent for RAG deficiency |
title_fullStr | Efficacy and safety of anti-CD45–saporin as conditioning agent for RAG deficiency |
title_full_unstemmed | Efficacy and safety of anti-CD45–saporin as conditioning agent for RAG deficiency |
title_short | Efficacy and safety of anti-CD45–saporin as conditioning agent for RAG deficiency |
title_sort | efficacy and safety of anti-cd45–saporin as conditioning agent for rag deficiency |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8322962/ https://www.ncbi.nlm.nih.gov/pubmed/32387109 http://dx.doi.org/10.1016/j.jaci.2020.04.033 |
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